NZ299077A

NZ299077A - Preparation of amorphous cefuroxime axetil (a cephalosporin derivative) by dissolving crystalline cefuroxim axetil in a highly polar solvent, typically dmso and/or dmf

Info

Publication number: NZ299077A
Application number: NZ299077A
Authority: NZ
Inventors: Khashayar Karimian; Mehrnoush Motamedi; Salvatore Zinghini
Original assignee: Apotex Inc
Priority date: 1996-07-26
Filing date: 1996-07-26
Publication date: 1998-06-26
Also published as: CA2211499A1; US5847118A

Description

<div class="application article clearfix" id="description"> New Zealand No. International No. 299077 PCT/ to be Entered after acceptance and publication Priority dates: 26.07.1996 Complete Specification Filed: 26.07.1996 Classification:^) C07D501/12//C07D501/46 Publication date: 26 June 1998 Journal No.: 1429 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of Invention: Methods for the manufacture of amorphous cefuroxime axetil Name, address and nationality of applicants) as in international application form: APOTEX INC, a Canadian corporation of 150 Signet Drive, Weston, Ontario, Canada M9L1T9 FORM 5 NEW ZEALAND S.9 Reg. 19(4) Fee: $260.00 299077 PATENTS ACT 1953 Provisional specification^) (if Number: any) and date(s) of filing; otherwise leave blank Date: complete specification METHODS FOR THE MANUFACTURE OF AMORPHOUS CEFUROXIME AXETIL l/WE APOTEX INC., a corporation organised and existing under the laws of Ontario, Canada, of 150 Signet Drive, Weston, Ontario, M9L 1T9, Canada hereby declare the invention for which l/we pray that a patent may be granted to me/us and the method by which it is to be performed, to be particularly described in and by the following statement:- invention Insert full name, full street address and nationality of (each) applicant Indicate if following page is numbered "1a" The following page is numbered "1a" 8.3.95 -1 - ' I 29907 la F1ELP of the invention This invention relates to novel processes for the manufacture of amorphous cefuroxime axetil. 10 15 BACKGROUND OF THE INVENTION Cefuroxime axetil, [R-6a,7p(Z)]]-3-[[(aminocarbonyl)oxy]methyl]-7-[[2-furanyl-(methoxyimino)acetylJamino]-8-oxo-5-thia-1-azabicyclo[4.2:0]oct-2-ene-2-carboxylic acid 1-acetoxyethyl ester is the 1-acethyloxyethyl ester of cefuroxime. Cefuroxime axetil can be classified as a member of the second generation cephalosporins and is 0-lactam antibacterial agent. Cefuroxime axetil has the following structure (I) & 20 25 CVI; N o \ O O O H H H r^s / o ( 9 o ^ A o ^ Y o (i) 30 O \.' V, •Oil / " ■? i \t t ' « 10 i I 299077 British Patent 1,571,683 discloses the preparation of cefuroxime axetil in crystalline form by precipitation from a solution of ethyl acetate with diethyl ether or diisopropyl ether. U.S. Patent 4,820,833 also describes the preparation of cefuroxime axetil in crystalline form by crystallization from ethyl acetate with subsequent addition of dissopropyl ether to obtain more crystalline material. U.S. Patent 4,820,833 also discloses that the amorphous form of cefuroxime axetil has higher bioavailability than crystalline cefuroxime axetil while maintaining adequate chemical stability upon storage. Accordingly, for commercial purpose the amorphous form is used rather than the-crystalline form. In US patent 4,820,833 (serial number 938,140), the crystalline product is 15 dissolved in an organic solvent and subsequently obtained in amorphous form by spray drying. Various examples of precipitation of amorphous cefuroxime axetil have also been provided. U.S. patent 5,013,833 which issued out of a divisional application of serial 20 number 938,140 describes the preparation of amorphous cefuroxime axetil by solvent precipitation of the product dissolved in an organic solvent (or a mixture thereof in water). In U.S. Patent 4,820,833 and U.S. Patent 5,013,833 the organic solvents include 25 ketones, alcohols, acetonitrile, tetrahydrofuran, dioxane, esters, chlorinated solvents, or a homogeneous mixture of at least two such solvents. 30 / i in. 29907 3 The precipitation processes referred to in U.S. patent 5,013,833 while producing cefuroxime axetil substantially in amorphous form have a number of disadvantages: 1. The use of very large volumes of a solvent such as dichloromethane (40 ml/g) and diisopropyl ether (32.5 ml/g) that by their toxicity and possibility of explosive peroxide formation may render the process not commercially feasible. 2. Precipitation of the product dissolved in acetone from water requires very elaborate experimental set up in the laboratory (filtration of the solution of the product prior to its addition to water or spray drying, high rate of stirring, exact rate of addition, continuous froth collection, the necessity to harvest the product immediately) which renders the reaction arduous and difficult to manage in a large scale manufacturing environment. In fact, even under a manageable laboratory environment, only a substantially amorphous product could be obtained. Further, the amount of the crystalline form varies substantially with slight changes in the above-mentioned parameters. It has now been surprisingly found that by dissolving crystalline cefuroxime axetil in a minimum volume of a highly polar organic solvent and adding the resulting solution to water or by dissolving crystalline cefuroxime axetil in a minimum volume of a highly polar organic solvent, adding water to the resulting solution and subsequently adding the resulting aqueous-organic solution to water, amorphous cefuroxime axetil could be obtained. The present processes have a number of major advantages over the existing procedures. ■ 4* 1 K j 25 2990 4 First, because of excellent solubilizing properties of the highly polar solvents used in this invention, there is no need for filtration of the solution containing the product prior to its precipitation in amorphous form. Filtration is crucial in the precipitation processes disclosed in U.S. Patent 5,013,833 because minute quantity of undissolved crystalline material could act as seeds and cause the precipitation of at least some of the material in its thermodynamically more stable crystalline form rather than the high energy amorphous form which may explain why only "substantially amorphous" material could be obtained by the previously disclosed precipitation processes. Second, very small volume of a highly polar solvent is requiredto achieve total dissolution, thus rendering the present processes more economical and environmentally safe. Third, the experimental conditions are simple and applicable to large scale production. Fourth, the present processes are reproducible and consistently afford amorphous [as examined by powder x-ray diffraction and IR spectrum (Figures 1 and 2)]. Fifth, the amorphous product generated by the processes of the present invention is highly pure and shows an acceptable ratio of the R and S diasteroisomers as defined by US Pharmacopoeia 23 (page 315). The mixture has improved solubility as compared with amorphous R isomer or amorphous S isomer alone. Sixth, the yields of the amorphous product obtained when practising the invention are very high and within the range of 84 to 96%. £ - •n1 •• V' BRIEF DESCRIPTION OF THE INVENTION 5 299071 Amorphous cefuroxime axetil is conveniently obtained by dissolving the crystalline form in a highly polar solvent such as and including highly polar solvents comprising sulfoxides and/or amides, for example DMSO, DMF, dimethyl acetamide, hexamethyl phosphoramide, or preferably formic acid and adding the resulting solution at 0-20°C to water with stirring. The precipitated amorphous material is filtered, pulped in small quantities of water and filtered (twice) to remove residual polar solvent. The damp cake is then dried with forced nitrogen at 3-35°C and then under vacuum at 35°C to obtain amorphous cefuroxime axetil in high yields. Figure 1 is a X-ray powder diffraction of amorphous cefuroxime as produced by the invention. Figure 2 is a IR spectrum of amorphous cefuroxime axetil. According to the present invention a process for the preparation of pure amorphous cefuroxime axetil is provided. The starting material in the present invention is crystalline cefuroxime axetil and more particulaHy a 50:50 mixture of R and S isomers of the carbon forming the ester function with the 2-carboxyl group of cefuroxime, which is commercially available. The amorphous cefuroxime axetil in accordance with the invention contains less than 0.6% of impurities. The major impurity associated with the process is usually in the range of 0.3-0.5% and is the anti form cefuroxime axetil in which the CH3-0- group of the oxime is cis with the furil ring: DETAILED DESCRIPTION OF THE INVENTION INTELLECTUAL PROPERTY OFFICE 0FN.Z. 24 APH ?S23 RECEIVED 25 t i 29907 The amorphous cefuroxime axetil produced according to the invention has been identified by powder x-ray diffraction and IR spectroscopy (Figures 1 and 2). 5 The transition temperature for the conversion of the amorphous form of cefuroxime axetil to its crystalline form appears to be low. Accordingly, due caution must be exercised to maintain the vacuum oven temperatures of below 45°C during the final drying stage. 10 The invention will be more fully understood by the following examples which illustrate the present invention, but are not to be considered limiting to the scope of the invention. 15 EXAMPLE 1 Cefuroxime axetil (5 g) was dissolved in 12 mi dimethyl sulfoxide by gentle heating. The resulting solution was added dropwise to deionized water (100 ml) cooled to 4°C with good mechanical stirring. A thick slurry formed which was 20 filtered and washed with a small quantity of ice cold deionized water. The damp cake was pulped in ice cold deionized water (30 ml) for 10 minutes, filtered and washed. Pulping was repeated once more. The cake was then dried under a stream of nitrogen for 42 hours and then dried under vacuum at 40-45°C for 48 hours. Yield 4.3 g (85%). /C '■* '■*?>'V ,y:t I 'MBGJSJi EXAMPLE 2 V* at> Cefuroxime axetil (5 g) was dissolved in 15 ml dimethyl sulfoxide by gentle 30 heating. Deionized water (6 ml) was added with good stirring. The resulting solution was added dropwise to deionized water (90 ml) cooled to 4°C with good mechanical stirring. A thick slurry formed which was filtered and washed with a 25 8 small quantity of ice cold deionized water. The damp cake was pulped in ice cold deionized water (30 ml) for 10 minutes, filtered and washed. Pulping was repeated once more. The cake was then dried under a stream of nitrogen for 42 hours and then dried under vacuum at 40-45°C for 48 hours. Yield 4.7 g (95 %). EXAMPLE 3 Cefuroxime axetil (5 g) was dissolved in 20 ml dimethyl formamide by gentle heating. The resulting solution was added dropwise to deionized water (150 ml) cooled to 4 °C with good mechanical stirring. A thick slurry formed which was filtered and washed with deionized water. The damp cake was pulped in deionized water (100 ml) for 30 minutes, filtered and washed. Pulping was repeated once more. The cake was then dried under vacuum at 40-45 °C for 48 hours. Yield 4.15 g (83 %). EXAMPLE 4 Cefuroxime axetil (5 g) was dissolved in 25 ml dimethyl formamide by gentle heating. Deionized water (9 ml) was added with good stirring. The resulting solution was added dropwise to deionized water (110 ml) cooled to 4 °C with good mechanical stirring. A thick slurry formed which was filtered and washed with a small quantity of ice cold deionized water. The damp cake was pulped in ice cold deionized water (30 ml) for 10 minutes, filtered and washed. Pulping was repeated once more. The cake was then dried under a stream of nitrogen for 42 hours and then dried under vacuum at 40-45 °C for 48 hours. Yield 4.4 g (89%). V \ 18 AUG 1996' i ^ ! 30 209077 EXAMPLE 5 5 Cefuroxime axetil (100 g) was dissolved in 152 ml 88% cold formic acid. The resulting solution was added dropwise to ice cold deionized water (2000 ml) with good mechanical stirring. A thick slurry formed which was filtered and washed with a small quantity of ice cold deionized water. The damp cake was pulped in ice cold deionized water (400 ml) for 10 minute, filtered and washed. Pulping 10 was repeated once more. The cake was then dried under a stream of nitrogen for 72 hours and then dried under vacuum at 40-45 °C for 48 hours. Yield 90 g (90%). 15 EXAMPLE 6 Cefuroxime axetil (100 g) was dissolved in 105 ml 96% cold formic acid. The resulting solution was added dropwise to ice cold deionized water (2000 ml) with good mechanical stirring. A thick slurry formed which was filtered and washed 20 with a small quantity of ice cold deionized water. The damp cake was pulped in ice cold deionized water (400 ml) for 10 minute, filtered and washed. Pulping was repeated once more. The cake was then dried under a stream of nitrogen for 72 hours and then dried under vacuum at 40-45 °C for 48 hours. Yield 90 g (90%). 25 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 10 WHAT WE CLAIM IS: ?OQQ77

1. Process of preparation of amorphous cefuroxime axetil which comprises the steps of: (a) dissolving crystalline cefuroxime axetil in a highly polar organic solvent and adding the resulting solution to water; or (b) dissolving crystalline cefuroxime axetil in a highly polar organic solvent, adding water to the resulting solution and subsequently adding the resulting aqueous-organic solution to water.

2. The process of claim 1 wherein the dissolution of crystalline cefuroxime axetil is carried out in a volume of solvent only sufficient to dissolve crystalline cefuroxime axetil.

3. The process of claim 1 or 2 wherein the highly polar solvent is a sulfoxide.

4. The process of claim 3 wherein the sulfoxide is dimethyl sulfoxide. The process of claim 1 or 2 wherein the highly polar solvent is an amide. The process of claim 5 wherein the amide is selected from the group consisting of dimethyl formamide, dimethyl acetamide, or hexamethyl phosphoramide. The process of claim 1 or 2 wherein the solvent is formic acid. INTELLECTUAL PROPffiTY OFFICE OF N 2. 2k AF" 15C3 RFP.FIVFn 299077 The process of claim 1 or 2 wherein the solvent is a homogeneous mixture of dimethyl sulfoxide and the amide. The process of claim 1 or 2 wherein the addition of the resulting solution to water is carried out between 0 to 40°C. The process of claim 9 wherein the addition is carried out between 0 to 4°C. j.a ha^E-&<5O. Potent Aftorrwyt for </div>